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DOI: 10.1055/s-2006-921385
© Georg Thieme Verlag Stuttgart · New York
Organdysfunktion und gestörte Mikrozirkulation des septischen Patienten
Organ Dysfunction and Disturbed Microcirculation in the Septic PatientPublication History
Publication Date:
03 February 2006 (online)
Zusammenfassung
Experimentelle und klinische Untersuchungen zur Pathogenese der Sepsis konnten zweifelsfrei nachweisen, dass Störungen der Mikrozirkulation eine wesentliche Determinante in der Manifestation der Organdysfunktion bis hin zum Organversagen darstellen. Von besonderer Bedeutung für sowohl die Entwicklung, als auch Progredienz des multiplen Organversagens, sind die Persistenz nutritiver Perfusionsstörungen mit fokaler Minderperfusion und Hypoxie vitaler Organe sowie die Aktivierung zellulärer und humoraler Systeme mit Dysbalance der Hämostase. Weiterhin sind Veränderungen der Hämorheologie mit Abnahme der Blutzelldeformabilität, Vasomotordysfunktion mit Umverteilung des Blutflusses sowie mitochondriale Sauerstoffutilisations-Störungen für die Gewebeschädigung und den Funktionsverlust verantwortlich. Im Gegensatz zu indirekten Methoden zur Erfassung der Mikrozirkulation (Laser-Doppler-Flowmetrie, HbO2-Spektroskopie und Kapnometrie) erlaubt das OPS (orthogonal polarization spectral)- und SDF (sidestream dark-field)-Imaging die direkte Visualisierung und quantitative Analyse mikrovaskulärer Netzwerke mit deren Perfusion und Leukozyten-Endothelzell-Interaktion. Erste Studien zeigen, dass die persistierende Minderperfusion der sublingualen Mukosa als einziger Parameter das Sepsis-bedingte Multiorganversagen mit Tod des Patienten hinreichend vorhersagt. Mit diesen nicht-invasiven bildgebenden Verfahren gilt es daher, in zukünftigen Untersuchungen den prädiktiven Wert von Mikrozirkulationsstörungen im Rahmen der Pathophysiologie von Sepsis und septischem Schock systematisch zu erarbeiten.
Abstract
There is a large body of evidence from both experimental and clinical studies that deteriorations of the microcirculation are major determinants for the manifestation of organ dysfunction and organ failure in sepsis. The persistence of nutritive perfusion failure with focal hypoperfusion and cellular hypoxia as well as the activation of cellular and humoral cascades are of outstanding importance for the development and progression of multiple organ failure. In addition, alterations in hemorheology with reduced blood cell deformability, vasomotor dysfunction and maldistribution of blood flow as well as deteriorations in mitochondrial oxygen utilisation contribute to tissue injury and loss of organ function. In contrast to indirect methods for assessment of the microcirculation (laser Doppler flowmetry, HbO2-spectroscopy and capnometry), OPS (orthogonal polarization spectral)- and SDF (sidestream dark-field)-imaging allow for direct visualisation and quantitative analysis of microvascular networks, including nutritive perfusion and leukocyte-endothelial cell interaction. Recent studies using OPS-imaging could demonstrate that persistent microcirculatory hypoperfusion of the sublingual mucosa was proportionally related to the occurence and severity of multiple organ failure. Further studies using these newer imaging techniques are required to characterize the predictive value of microcirculatory alterations for the outcome in sepsis and septic shock.
Schlüsselwörter
Entzündung - Mikrozirkulation; - Perfusionsversagen - Hypoxie - bildgebende Verfahren
Key words
Inflammation - microcirculation - perfusion failure - hypoxia - imaging techniques
Literatur
- 1 Lam C, Tyml K, Martin C, Sibbald W. Microvascular perfusion is impaired in a rat model of normotensive sepsis. J Clin Invest. 1994; 94 2077-2083
- 2 De Backer D, Creteur J, Preiser J C, Dubois M J, Vincent J L. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med. 2002; 166 98-104
- 3 Sakr Y, Dubois M J, De Backer D, Creteur J, Vincent J L. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med. 2004; 32 1825-1831
- 4 Ince C. The microcirculation is the motor of sepsis. Crit Care. 2005; 9 S 13-S 19
- 5 Spronk P E, Zandstra D F, Ince C. Bench-to-bedside review: sepsis is a disease of the microcirculation. Crit Care. 2004; 8 462-468
- 6 Buwalda M, Ince C. Opening the microcirculation: can vasodilators be useful in sepsis?. Intensive Care Med. 2002; 28 1208-1217
- 7 Piagnerelli M, Boudjeltia K Z, Vanhaeverbeek M, Vincent J L. Red blood cell rheology in sepsis. Intensive Care Med. 2003; 29 1052-1061
- 8 Ince C, Sinaasappel M. Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med. 1999; 27 1369-1377
- 9 Ellis C G, Bateman R M, Sharpe M D, Sibbald W J, Gill R. Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis. Am J Physiol Heart Circ Physiol. 2002; 282 H 156-H 164
- 10 Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies N A, Cooper C E, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002; 360 219-223
- 11 Fink M P. Bench-to-bedside review: Cytopathic hypoxia. Crit Care. 2002; 6 491-499
- 12 Eipel C, Bordel R, Nickels R M, Menger M D, Vollmar B. Impact of leukocytes and platelets in mediating hepatocyte apoptosis in a rat model of systemic endotoxemia. Am J Physiol Gastrointest Liver Physiol. 2004; 286 G 769-G 776
- 13 Amaral A, Opal S M, Vincent J L. Coagulation in sepsis. Intensive Care Med. 2004; 30 1032-1040
- 14 Hoffmann J N, Vollmar B, Laschke M W, Fertmann J M, Jauch K W, Menger M D. Microcirculatory alterations in ischemia-reperfusion injury and sepsis: effects of activated protein C and thrombin inhibition. Crit Care. 2005; 9 S 33-S 37
- 15 Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M. Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001; 345 1368-1377
- 16 Yodice P C, Astiz M E, Kurian B M, Lin R Y, Rackow E C. Neutrophil rheologic changes in septic shock. Am J Respir Crit Care Med. 1997; 155 38-42
- 17 Mohandas N, Chasis J A. Red blood cell deformability, membrane material properties and shape: regulation by transmembrane, skeletal and cytosolic proteins and lipids. Semin Hematol. 1993; 30 171-192
- 18 Lau Y T, Hsieh C C, Liu M S, Hwang T L, Chen M F, Cheng H S. Erythrocyte Ca2+ pump is defective during sepsis. Circ Shock. 1994; 44 121-125
- 19 Todd J C, Mollitt D L. Effect of sepsis on erythrocyte intracellular calcium homeostasis. Crit Care Med. 1995; 23 459-465
- 20 Suzuki Y, Nakajima T, Shiga T, Maeda N. Influence of 2,3-diphosphoglycerate on the deformability of human erythrocytes. Biochim Biophys Acta. 1990; 1029 85-90
- 21 Drost E M, Kassabian G, Meiselman H J, Gelmont D, Fisher T C. Increased rigidity and priming of polymorphonuclear leukocytes in sepsis. Am J Respir Crit Care Med. 1999; 159 1696-1702
- 22 Kirschenbaum L A, Aziz M, Astiz M E, Saha D C, Rackow E C. Influence of rheologic changes and platelet-neutrophil interactions on cell filtration in sepsis. Am J Respir Crit Care Med. 2000; 161 1602-1607
- 23 Kirschenbaum L A, Adler D, Astiz M E, Barua R S, Saha D, Rackow E C. Mechanisms of platelet-neutrophil interactions and effects on cell filtration in septic shock. Shock. 2002; 17 508-512
- 24 Berliner A S, Shapira I, Rogowski O, Sadees N, Rotstein R, Fusman R, Avitzour D, Cohen S, Arber N, Zeltser D. Combined leukocyte and erythrocyte aggregation in the peripheral venous blood during sepsis. An indication of commonly shared adhesive protein(s). Int J Clin Lab Res. 2000; 30 27-31
- 25 Claster S, Chiu D T, Quintanilha A, Lubin B. Neutrophils mediate lipid peroxidation in human red cells. Blood. 1984; 64 1079-1084
- 26 Davies K J, Goldberg A L. Oxygen radicals stimulate intracellular proteolysis and lipid peroxidation by independent mechanisms in erythrocytes. J Biol Chem. 1987; 262 8220-8226
- 27 Berezina T L, Zaets S B, Machiedo G W. Alterations of red blood cell shape in patients with severe trauma. J Trauma. 2004; 57 82-87
- 28 Langenfeld J E, Livingston D H, Machiedo G W. Red cell deformability is an early indicator of infection. Surgery. 1991; 110 398-403
- 29 Chung T W, O'Rear E A, Whitsett T L, Hinshaw L B, Smith M A. Survival factors in a canine septic shock model. Circ Shock. 1991; 33 178-182
- 30 Gocan N C, Scott J A, Tyml K. Nitric oxide produced via neuronal NOS may impair vasodilatation in septic rat skeletal muscle. Am J Physiol Heart Circ Physiol. 2000; 278 H 1480-H 1489
- 31 Wu F, Cepinskas G, Wilson J X, Tyml K. Nitric oxide attenuates but superoxide enhances iNOS expression in endotoxin- and IFN-gamma-stimulated skeletal muscle endothelial cells. Microcirculation. 2001; 8 415-425
- 32 Beasley D, Eldridge M. Interleukin-1 beta and tumor necrosis factor-alpha synergistically induce NO synthase in rat vascular smooth muscle cells. Am J Physiol. 1994; 266 R 1197-R 1203
- 33 Cunha F Q, Assreuy J, Moss D W, Rees D, Leal L M, Moncada S, Carrier M, O'Donnell C A, Liew F Y. Differential induction of nitric oxide synthase in various organs of the mouse during endotoxaemia: role of TNF-alpha and IL-1-beta. Immunology. 1994; 81 211-215
- 34 Hollenberg S M, Cunnion R E, Zimmerberg J. Nitric oxide synthase inhibition reverses arteriolar hyporesponsiveness to catecholamines in septic rats. Am J Physiol. 1993; 264 H 660-H 663
- 35 Gunnett C A, Chu Y, Heistad D D, Loihl A, Faraci F M. Vascular effects of LPS in mice deficient in expression of the gene for inducible nitric oxide synthase. Am J Physiol. 1998; 275 H 416-H 421
- 36 Hollenberg S M, Broussard M, Osman J, Parrillo J E. Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase. Circ Res. 2000; 86 774-778
- 37 Booke M, Hinder F, McGuire R, Traber L D, Traber D L. Selective inhibition of inducible nitric oxide synthase: effects on hemodynamics and regional blood flow in healthy and septic sheep. Crit Care Med. 1999; 27 162-167
- 38 Wanecek M, Weitzberg E, Rudehill A, Oldner A. The endothelin system in septic and endotoxin shock. Eur J Pharmacol. 2000; 407 1-15
- 39 Figueras-Aloy J, Gomez L, Rodriguez-Miguelez J M, Jordan Y, Salvia M D, Jimenez W, Carbonell-Estrany X. Plasma nitrite/nitrate and endothelin-1 concentrations in neonatal sepsis. Acta Paediatr. 2003; 92 582-587
- 40 Clemens M G, Zhang J X. Regulation of sinusoidal perfusion: in vivo methodology and control by endothelins. Semin Liver Dis. 1999; 19 383-396
- 41 Gundersen Y, Corso C O, Leiderer R, Dorger M, Lilleaasen P, Aasen A O, Messmer K. The nitric oxide donor sodium nitroprusside protects against hepatic microcirculatory dysfunction in early endotoxaemia. Intensive Care Med. 1998; 24 1257-1263
- 42 Lopez A, Lorente J A, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, Silverman M S, Takala J, Donaldson J, Arneson C, Grove G, Grossman S, Grover R. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med. 2004; 32 21-30
- 43 Torres J, Wilson M T. Interaction of cytochrome-c oxidase with nitric oxide. Methods Enzymol. 1996; 269 3-11
- 44 Borutaite V, Matthias A, Harris H, Moncada S, Brown G C. Reversible inhibition of cellular respiration by nitric oxide in vascular inflammation. Am J Physiol Heart Circ Physiol. 2001; 281 H 2256-H 2260
- 45 Cines D B, Pollak E S, Buck C A, Loscalzo J, Zimmerman G A, McEver R P, Pober J S, Wick T M, Konkle B A, Schwartz B S, Barnathan E S, McCrae K R, Hug B A, Schmidt A M, Stern D M. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998; 91 3527-3561
- 46 Aird W C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003; 101 3765-3777
- 47 Vallet B, Wiel E. Endothelial cell dysfunction and coagulation. Crit Care Med.. 2001; 29 S 36-S 41
- 48 Gross P L, Aird W C. The endothelium and thrombosis. Semin Thromb Hemost. 2000; 26 463-478
- 49 Rosenberg R D, Aird W C. Vascular-bed-specific hemostasis and hypercoagulable states. N Engl J Med. 1999; 340 1555-1564
- 50 Ferro T, Neumann P, Gertzberg N, Clements R, Johnson A. Protein kinase C-alpha mediates endothelial barrier dysfunction induced by TNF-alpha. Am J Physiol Lung Cell Mol Physiol. 2000; 278 L 1107-L 1117
- 51 Tiruppathi C, Naqvi T, Sandoval R, Mehta D, Malik A B. Synergistic effects of tumor necrosis factor-alpha and thrombin in increasing endothelial permeability. Am J Physiol Lung Cell Mol Physiol. 2001; 281 L 958-L 968
- 52 Green J, Doughty L, Kaplan S S, Sasser H, Carcillo J A. The tissue factor and plasminogen activator inhibitor type-1 response in pediatric sepsis-induced multiple organ failure. Thromb Haemost. 2002; 87 218-223
- 53 Moore K L, Andreoli S P, Esmon N L, Esmon C T, Bang N U. Endotoxin enhances tissue factor and suppresses thrombomodulin expression of human vascular endothelium in vitro. J Clin Invest. 1987; 79 124-130
- 54 Bombeli T, Karsan A, Tait J F, Harlan J M. Apoptotic vascular endothelial cells become procoagulant. Blood. 1997; 89 2429-2442
- 55 Bombeli T, Schwartz B R, Harlan J M. Endothelial cells undergoing apoptosis become proadhesive for nonactivated platelets. Blood. 1999; 93 3831-3838
- 56 Cohen J. The immunopathogenesis of sepsis. Nature. 2002; 420 885-891
- 57 Schafer T, Scheuer C, Roemer K, Menger M D, Vollmar B. Inhibition of p53 protects liver tissue against endotoxin-induced apoptotic and necrotic cell death. FASEB J. 2003; 17 660-667
- 58 Lopez S, Prats N, Marco A J. Expression of E-selectin, P-selectin, and intercellular adhesion molecule-1 during experimental murine listeriosis. Am J Pathol. 1999; 155 1391-1397
- 59 McIntyre T M, Prescott S M, Weyrich A S, Zimmerman G A. Cell-cell interactions: leukocyte-endothelial interactions. Curr Opin Hematol. 2003; 10 150-158
- 60 Ebnet K, Kaldjian E P, Anderson A O, Shaw S. Orchestrated information transfer underlying leukocyte endothelial interactions. Annu Rev Immunol. 1996; 14 155-177
- 61 Jaeschke H, Smith C W. Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol. 1997; 61 647-653
- 62 Jaeschke H, Fisher M A, Lawson J A, Simmons C A, Farhood A, Jones D A. Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model. J Immunol. 1998; 160 3480-3486
-
63 Slotta J E, Scheuer C, Menger M D, Vollmar B. Immunostimulatory CpG-oligodeoxynucleotides (CpG-ODN) protect against endotoxin-induced liver damage. J Hepatol 2005 Nov 23
- 64 Leo R, Pratico D, Iuliano L, Pulcinelli F M, Ghiselli A, Pignatelli P, Colavita A R, FitzGerald G A, Violi F. Platelet activation by superoxide anion and hydroxyl radicals intrinsically generated by platelets that had undergone anoxia and then reoxygenated. Circulation. 1997; 95 885-891
- 65 Weyrich A S, Elstad M R, McEver R P, McIntyre T M, Moore K L, Morrissey J H, Prescott S M, Zimmerman G A. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest. 1996; 97 1525-1534
- 66 Faint R W. Platelet-neutrophil interactions: their significance. Blood Rev. 1992; 6 83-91
- 67 Vincent J L, Yagushi A, Pradier O. Platelet function in sepsis. Crit Care Med. 2002; 30 S 313-S 317
- 68 Nagata K, Tsuji T, Todoroki N, Katagiri Y, Tanoue K, Yamazaki H, Hanai N, Irimura T. Activated platelets induce superoxide anion release by monocytes and neutrophils through P-selectin (CD62). J Immunol. 1993; 151 3267-3273
- 69 Palabrica T, Lobb R, Furie B C, Aronovitz M, Benjamin C, Hsu Y M, Sajer S A, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature. 1992; 359 848-851
- 70 Andonegui G, Trevani A S, Lopez D H, Raiden S, Giordano M, Geffner J R. Inhibition of human neutrophil apoptosis by platelets. J Immunol. 1997; 158 3372-3377
- 71 Yu Z, Ohtaki Y, Kai K, Sasano T, Shimauchi H, Yokochi T, Takada H, Sugawara S, Kumagai K, Endo Y. Critical roles of platelets in lipopolysaccharide-induced lethality: effects of glycyrrhizin and possible strategy for acute respiratory distress syndrome. Int Immunopharmacol. 2005; 5 571-580
- 72 Hewett J A, Schultze A E, VanCise S, Roth R A. Neutrophil depletion protects against liver injury from bacterial endotoxin. Lab Invest. 1992; 66 347-361
- 73 Steeber D A, Tang M L, Green N E, Zhang X Q, Sloane J E, Tedder T F. Leukocyte entry into sites of inflammation requires overlapping interactions between the L-selectin and ICAM-1 pathways. J Immunol. 1999; 163 2176-2186
- 74 Munoz F M, Hawkins E P, Bullard D C, Beaudet A L, Kaplan S L. Host defense against systemic infection with Streptococcus pneumoniae is impaired in E-, P-, and E-/P-selectin-deficient mice. J Clin Invest. 1997; 100 2099-2106
- 75 Gutierrez-Ramos J C, Bluethmann H. Molecules and mechanisms operating in septic shock: lessons from knock out mice. Immunol Today. 1997; 18 329-334
- 76 Vollmar B, Pradarutti S, Nickels R M, Menger M D. Age-associated loss of immunomodulatory protection by granulocyte-colony stimulating factor in endotoxic rats. Shock. 2002; 18 348-354
- 77 Hoffmann J N, Vollmar B, Inthorn D, Schildberg F W, Menger M D. A chronic model for intravital microscopic study of microcirculatory disorders and leukocyte/endothelial cell interaction during normotensive endotoxemia. Shock. 1999; 12 355-364
- 78 Ring A, Stremmel W. The hepatic microvascular responses to sepsis. Semin Thromb Hemost. 2000; 26 589-594
- 79 Drazenovic R, Samsel R W, Wylam M E, Doerschuk C M, Schumacker P T. Regulation of perfused capillary density in canine intestinal mucosa during endotoxemia. J Appl Physiol. 1992; 72 259-265
- 80 Sielenkamper A W, Meyer J, Kloppenburg H, Eicker K, Van Aken H. The effects of sepsis on gut mucosal blood flow in rats. Eur J Anaesthesiol. 2001; 18 673-678
- 81 Nakajima Y, Baudry N, Duranteau J, Vicaut E. Microcirculation in intestinal villi: a comparison between hemorrhagic and endotoxin shock. Am J Respir Crit Care Med. 2001; 164 1526-1530
- 82 Bateman R M, Sharpe M D, Ellis C G. Bench-to-bedside review: microvascular dysfunction in sepsis-hemodynamics, oxygen transport, and nitric oxide. Crit Care. 2003; 7 359-373
- 83 Anning P B, Sair M, Winlove C P, Evans T W. Abnormal tissue oxygenation and cardiovascular changes in endotoxemia. Am J Respir Crit Care Med. 1999; 159 1710-1715
- 84 James P E, Madhani M, Roebuck W, Jackson S K, Swartz H M. Endotoxin-induced liver hypoxia: defective oxygen delivery versus oxygen consumption. Nitric Oxide. 2002; 6 18-28
- 85 Walley K R. Heterogeneity of oxygen delivery impairs oxygen extraction by peripheral tissues: theory. J Appl Physiol. 1996; 81 885-894
- 86 Goldman D, Bateman R M, Ellis C G. Effect of sepsis on skeletal muscle oxygen consumption and tissue oxygenation: interpreting capillary oxygen transport data using a mathematical model. Am J Physiol Heart Circ Physiol. 2004; 287 H 2535-H 2544
- 87 Fink M P. Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis. Crit Care Clin. 2001; 17 219-237
- 88 Freedlander S O, Lenhart C H. Clinical observations on the capillary circulation. Arch Intern Med. 1922; 29 12-32
- 89 Weinberg J R, Boyle P, Thomas K, Murphy K, Tooke J E, Guz A. Capillary blood cell velocity is reduced in fever without hypotension. Int J Microcirc Clin Exp. 1991; 10 13-19
- 90 Marik P E. Regional carbon dioxide monitoring to assess the adequacy of tissue perfusion. Curr Opin Crit Care. 2005; 11 245-251
- 91 Girardis M, Rinaldi L, Busani S, Flore I, Mauro S, Pasetto A. Muscle perfusion and oxygen consumption by near-infrared spectroscopy in septic-shock and non-septic-shock patients. Intensive Care Med. 2003; 29 1173-1176
- 92 Astiz M E, DeGent G E, Lin R Y, Rackow E C. Microvascular function and rheologic changes in hyperdynamic sepsis. Crit Care Med. 1995; 23 265-271
- 93 Kirschenbaum L A, Astiz M E, Rackow E C, Saha D C, Lin R. Microvascular response in patients with cardiogenic shock. Crit Care Med. 2000; 28 1290-1294
- 94 Neviere R, Mathieu D, Chagnon J L, Lebleu N, Millien J P, Wattel F. Skeletal muscle microvascular blood flow and oxygen transport in patients with severe sepsis. Am J Respir Crit Care Med. 1996; 153 191-195
- 95 Groner W, Winkelman J W, Harris A G, Ince C, Bouma G J, Messmer K, Nadeau R G. Orthogonal polarization spectral imaging: a new method for study of the microcirculation. Nat Med. 1999; 5 1209-1212
- 96 Spronk P E, Ince C, Gardien M J, Mathura K R, Oudemans-van Straaten H M, Zandstra D F. Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet. 2002; 360 1395-1396
- 97 Weil M H, Nakagawa Y, Tang W, Sato Y, Ercoli F, Finegan R, Grayman G, Bisera J. Sublingual capnometry: a new noninvasive measurement for diagnosis and quantitation of severity of circulatory shock. Crit Care Med. 1999; 27 1225-1229
- 98 De Backer D, Creteur J. Regional hypoxia and partial pressure of carbon dioxide gradients: what is the link?. Intensive Care Med. 2003; 29 2116-2118
Prof. Dr. med. B. Vollmar
Abteilung für Experimentelle Chirurgie · Universität Rostock
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18055 Rostock
Phone: +49/381/4 94 62 20
Fax: +49/381/4 94 62 22
Email: brigitte.vollmar@med.uni-rostock.de